Esophageal activity modulated obesity therapy

ABSTRACT

Methods and devices for delivering electrical stimulation to the sympathetic nervous system in response to the onset of eating. In some methods, swallowing is detected which then initiates a dose of stimulation which can vary in intensity, frequency, or both over the dose length. In some methods, the dose length is between about one quarter hour and one hour. The dose frequency may increase, hold steady, then decrease over the dose duration so as to mimic the response of the gut stretch and nutrient receptors to receiving food. The dose can drive biomarkers indicative of eating, for example glucagon, glucose, FFA or glycerol to at least about half of their normal post eating levels and then stop so as to retain stimulation effectiveness for subsequent doses and to prolong battery life.

CROSS REFERENCE TO RELATED APPLICATION

This application claims priority from U.S. provisional application61/170,964, filed Apr. 20, 2009, which is herein incorporated byreference in its entirety.

FIELD OF THE INVENTION

The invention is related generally to neuromodulation, in particular tostimulating the sympathetic nervous system to treat obesity.

BACKGROUND

Obesity results from an imbalance between food intake and energyexpenditure, such that there is a net increase in fat reserves.Excessive food intake, reduced energy expenditure, or both maycontribute to this in balance. Clinically, obesity is defined relativeto body mass index (BMI), a measure of body weight to body surface(kg/m²). A normal BMI is considered to be in the range from greater than30 kg/m². A BMI in the range from 25-30 is considered overweight, whileobese is classified as having a BMI >30. Obesity is classified into 3subcategories: Class I—moderate; Class II—severe; and Class III verysevere.

It is well established that patients with elevated BMIs are at increasedrisk for a variety of diseases including hypertension and cardiovasculardisease, kidney disease, diabetes, dyslipidemia, sleep apnea, andorthopedic problems. Obesity has become pandemic in the U.S. with aprevalence exceeding 30%. The increased demand on health care resourcesdue to obesity and the health problems associated with it are estimatedin the U.S. to exceed $200 billion annually.

Appetite and satiety, which control food intake, are partly regulated bythe hypothalamus region of the brain. Energy expenditure is alsocontrolled in part by the hypothalamus. The hypothalamus regulates theautonomic nervous system of which there are two branches, thesympathetic and the parasympathetic. The sympathetic nervous systemgenerally prepares the body for action by increasing heart rate, bloodpressure, and metabolism. The parasympathetic system prepares the bodyfor rest by lowering heart rate, lowering blood pressure, andstimulating digestion. Destruction of the lateral hypothalamus resultsin hunger suppression, reduced food intake, weight loss, and increasedsympathetic activity. In contrast, destruction of the ventromedialnucleus of the hypothalamus results in suppression of satiety, excessivefood intake, weight gain, and decreased sympathetic activity.

The splanchnic nerves carry sympathetic neurons that innervate theorgans of digestion and the adrenal glands, while the vagus nervecarries parasympathetic neurons that innervate the digestive system, andas experiments involving hypothalamic destruction have shown, thoseneurons involved in the feeding and weight gain response.

Experimental and observational evidence suggests that there is areciprocal relationship between sympathetic nervous system activity andfood intake, with an increase in sympathetic activity generally leadingto a reduction in food intake. These effects are mediated by specificneuropeptides (e.g., neuropeptide Y, galanin) known to decreasesympathetic activity, which in turn triggers an increase food intake.Other peptides such as cholesystokinin, leptin, and enterostatin,increase sympathetic activity, thus decreasing food intake. Ghrelin is apeptide that is secreted by the stomach and which is associated withhunger. Peak plasma levels of this peptide occur just prior to mealtime,and ghrelin levels are increased after weight loss. Sympathetic activitycan suppress ghrelin secretion. PYY is a hormone released from theintestine that also plays a role in satiety. PYY levels increase aftermeal ingestion. Sympathetic activity can increase PYY levels. Similarly,drugs such as nicotine, ephedrine, caffeine, subitramine,dexfenfluramine, which lead to an increase in sympathetic activity, alsoreduce food intake.

Appetite is stimulated by various psychosocial factors, but also by lowblood glucose levels, as well as mechanical receptors in thegastrointestinal tract. For example, cells in the hypothalamus that aresensitive to glucose levels are thought to play a role in the hungerresponse, increasing the sensation of hunger as glucose levels decrease.In response, activation of the sympathetic nervous system leads to anincrease in plasma glucose levels. Similarly, a feeling of satiety canbe promoted by distention of the stomach and delayed gastric emptying.Sympathetic nerve activity reduces gastric and duodenal motility, causesgastric distention, and can increase contraction of the pyloricsphincter, which can result in distention and delayed emptying of thestomach contents.

The sympathetic nervous system also plays a role in energy expenditureand thus the tendency towards obesity. Genetically inherited obesity inrodents is characterized by decreased sympathetic activity in adiposetissue and other peripheral organs. Catecholamines and cortisol, whichare released by the sympathetic nervous system, cause a dose-dependentincrease in resting energy expenditure. In humans, a negativecorrelation between body fat and plasma catecholamine levels has beenreported.

Over- or under-feeding lean human subjects can have significant effectson sympathetic nervous system activation and energy expenditure. Forexample, weight loss in obese subjects is associated with a compensatorydecrease in energy expenditure, which promotes regaining previously lostweight, a common problem that limits the effectiveness of classic dietand exercise weight loss programs. Conversely, drugs that activate thesympathetic nervous system, such as ephedrine, caffeine, or nicotine,are known to increase energy expenditure. Smokers are known to havelower body fat stores and increased energy expenditure relative tonon-smokers. Weight gain is a commonly reported consequence of quittingsmoking. The sympathetic nervous system also plays an important role inregulating energy substrates such as fat and carbohydrate. Metabolism ofglycogen and fat, needed to support increased energy expenditure, isincreased by sympathetic activation.

Animal research shows that acute electrical activation of the splanchnicnerves causes a variety of physiologic changes. Electrical activation ofa single splanchnic nerve in dogs and cows causes a frequency dependentincrease in catecholamine, dopamine, and cortisol secretion, andcirculating plasma levels of these compounds that lead to increasedenergy expenditure can be achieved. In adrenalectomized pigs, cows, anddogs, acute single splanchnic nerve activation causes increased bloodglucose levels with concomitant reduction in liver glycogen stores. Indogs, single splanchnic nerve activation causes increased pyloricsphincter tone and decreased duodenal motility, reducing the rate offood passage through the gastrointestinal tract, and in turn leading toa sensation of satiety. Moreover, sympathetic, and specificallysplanchnic nerve, activation can result in suppression of insulin andleptin hormone secretion.

First-line therapy for obesity treatment is typically behaviormodification involving reduced food intake and/or increased exercise.However, these approaches frequently fail and behavioral treatment iscommonly supplemented by administration of pharmacologic agents known toreduce appetite and/or increase energy expenditure. Commonly usedpharmacologic agents include dopamine and a dopamine analogues,acetylcholine and cholinesterase inhibitors. Pharmacologic therapy istypically delivered orally. However, treating obesity with drugsfrequently results in undesirable side effects, including systemiceffects such as tachycardia, sweating, and hypertension. In addition,tolerance can develop such that the response to the drug is reduced evenone higher doses are used.

More radical forms of therapy involve surgical intervention. In general,these procedures are designed to reduce the size of the stomach and/orreroute the gastrointestinal tract to substantially avoid the stomach,the net effect being either a reduction in the amount of food that canbe consumed before feeling full, reduction in absorption, or both.Representative procedures include gastric bypass surgery and gastricbanding. While these procedures can be effective in treating obesity,they are highly invasive, require significant lifestyle changes, and mayhave significant postoperative complications.

More recent experimental forms for treating obesity have involvedelectrical stimulation of the stomach (gastric pacing) and the vagusnerve (parasympathetic stimulation). These therapies make use of a pulsegenerator to electrically stimulate the stomach or nerves via implantedelectrodes. The object of these therapies is to reduce food intakethrough the promotion of satiety and/or reduction of appetite. Forexample, U.S. Pat. No. 5,423,872 (Cigaina) discloses a method fortreating eating disorders by electrically pacing the stomach. Similarly,U.S. Pat. No. 5,263,480 (Wernicke) discloses a method for treatingobesity by likely activating the vagus nerve. However, while thesemethods are suggested to be effective in reducing food intake, neitheris believed to affect energy expenditure.

SUMMARY

There are significant limitations in prior art methods and apparatusused in treating obesity that limit their effectiveness. In first linetherapeutic approaches, such as simple regulation of food intakecombined with exercise, compliance and discipline are primary pitfalls.In neuromodulatory therapies, the application of electrical signals tonerves in order to regulate food consumption and/or energy expenditure,are not necessarily linked to the subject's individual physiology, andthus may fail to maximize the benefits of this approach as an obesitytreatment method. In addition, essentially all prior art neuromodulatorymethods are subject to limitations inherent to neurons, specifically thefact that chronic stimulation leads to neural accommodation, and thusreduced effectiveness of the neuromodulation program.

What are needed, therefore, are systems and methods for the treatment ofobesity that overcome compliance problems inherent in first-linetherapeutic approaches such as diet and exercise programs. In addition,what are needed are systems and methods of controlling obesity that areeffectively self-regulating, such that the need for patient compliancebecomes either irrelevant or significantly reduced. In particular,systems and methods of treating obesity that self-regulate in responseto normal physiological parameters, for example timing of meals and ortiming of rest or sleep periods, will be able to avoid compliance issuesthat arise when the subject is left in control of a diet and/or exerciseregimes.

Without being limited by theory, it is believed that to achieve weightloss over time, the generation of false satiety signals coincident withthe timing of normal body functions will either escape, or substantiallyavoid, some of the effects of habituation (i.e., neural accommodation)to a therapeutic signal. In particular limiting the use ofneuromodulation to induce satiety to periods slightly preceding orconcomitant with eating (i.e., meals) will be effective to reduce foodintake. Similarly, using a stimulatory pattern designed to increasemetabolism during intervals between meals will be effective to furtherenhance weight loss by increasing energy expenditure. In effect, thesemethods provides a dual stimulatory program that (a) mimics satiety at atime most effective to reduce food consumption; and (b) mimics exercise,by increasing energy expenditure during intervals between periods ofnutrient consumption. Furthermore, it is believed that by generating afalse satiety signal during food intake, a “safe harbor” will providedby effectively “hiding” the neuromodulatory signal behind a naturalevent, in turn producing a more pronounced satiety signal and in turnmore effectively reducing food intake.

The present invention includes methods and apparatus for treatingobesity, and potentially other disorders by electrically stimulating thesympathetic nervous system in response to detection of a period ofnutrient consumption in such a way as to simulate satiety, and duringthe intervals between successive periods of food intake in such a way asto increase energy expenditure. By differentially applying stimulatorypatterns configured to either mimic satiety, or increase energyexpenditure, obesity can be more successfully treated than would bepossible using a single stimulatory paradigm. Further, the inventionprovides that the alternating “satiety” and “energy” programs areregulated automatically, removing compliance issues that occur when asubject is left to regulate their own obesity therapy program.

The present invention includes a method for treating obesity or otherdisorders by electrically activating the sympathetic nervous system.Satiety can be induced by stimulating afferent fibers in the sympatheticnervous system, and in particular fibers in the splanchnic nerve.Likewise, activating efferent fibers can be used to increase energyexpenditure and reducing food intake.

Stimulation is accomplished using a pulse generator and electrodesimplanted near, or attached to, various areas of the sympathetic nervoussystem, such as the sympathetic chain ganglia, the splanchnic nerves(greater, lesser, least), or the peripheral ganglia (e.g., celiac,mesenteric). Ideally, the obesity therapy can employ electricalactivation of the sympathetic nervous system that innervates thedigestive system, adrenals, and abdominal adipose tissue, such as thesplanchnic nerves and/or celiac ganglia.

A method of obesity treatment may reduce food intake by a variety ofmechanisms, including general increased sympathetic system activationand increasing plasma glucose levels upon activation. Satiety may beproduced through direct affects on the pylorus and duodenum that causestomach distension and delayed stomach emptying. In addition, limitingghrelin secretion can be used to reduce food intake.

A method of obesity treatment may also increase energy expenditure bycausing catecholamine, cortisol, and dopamine release from the adrenalglands, and may be titrated to vary the rate of release of thesehormones. Fat and carbohydrate metabolism, which is also increased bysympathetic nerve activation, will accompany the increased energyexpenditure. Other hormonal effects induced by this therapy may includereduced insulin secretion. Alternatively, this method may be used tonormalize catecholamine levels, which are reduced with weight gain.

Electrical sympathetic activation for treating obesity is ideallyaccomplished without causing a rise in mean arterial blood pressure(MAP). During activation therapy, a sinusoidal-like fluctuation in theMAP may occur with an average MAP that is within safe limits.Alternatively, an alpha sympathetic receptor blocker, such as prazosin,could be used to blunt the increase in MAP.

Electrical modulation (inhibition or activation) of the sympatheticnerves might also be used to treat other eating disorders such asanorexia or bulimia. For example, inhibition of the sympathetic nervesmay be useful in treating anorexia. Electrical modulation of thesympathetic nerves may also be used to treat gastrointestinal diseasessuch as peptic ulcers, esophageal reflux, gastroparesis, and irritablebowel syndrome. For example, stimulation of the splanchnic nerves thatinnervate the large intestine may reduce the symptoms of irritable bowelsyndrome, characterized by diarrhea. Pain may also be treated byelectric nerve modulation of the sympathetic nervous system, as certainpain neurons are carried in the sympathetic nerves. This therapy mayalso be used to treat type II diabetes. These conditions may requirevarying degrees of inhibition or stimulation.

The present invention provides that satiety mimicking signals areapplied to the sympathetic nervous in response to swallowing, or someother physiological parameter directly associated with the intake offood, or temporally coordinated with the perception that food is, or isabout to be, consumed. Between periods of feeding, the inventionprovides that signals designed to increase energy expenditure areapplied to the sympathetic nervous system. Collectively, the inventionprovides increased effectiveness in inducing satiety, as well asincreasing energy expenditure, which together provide that the inventionimproves on prior methods and apparatus for treating obesity. Inaddition, the neural stimulation paradigms in the present inventionreduce the likelihood of neural accommodation, and can be titrated tomaximize effectiveness of the generated signals with respect to reducingfood intake and increasing energy expenditure.

Therefore, in some embodiments a method of modulating a component of thenervous system of a mammal, the method comprising: providing a sensor,wherein the sensor is configured to produce a first sensor output signalassociated with the onset of a period of nutrient consumption, and asecond sensor output signal, associated with the end of a period ofnutrient consumption; providing a stimulator configured to output afirst therapeutic signal in response to the first sensor output signal,and a second therapeutic signal in response to the second sensor outputsignal; wherein applying the first therapeutic signal to a firstcomponent of the nervous system is effective to mimic satiety in themammal; and wherein applying the second therapeutic signal to a secondcomponent of the nervous system is effective to produce an increase inenergy expenditure in the mammal.

In some embodiments, the sensor is configured to produce the firstsensor output signal in response to at least one of swallowing, a bloodglucose level, a neurological signal associated with olfaction, astomach pH level, an electrical impedance of saliva, anelectromyographic signal in the esophagus, and a change in intrathoracicpressure.

In some embodiments, the sensor is configured to produce the secondsensor output signal in response to at least one of cessation ofswallowing, a blood glucose level, a neurological signal associated withloss of an olfactory signal, a stomach pH level, an electrical impedanceof saliva, an electromyographic signal in the esophagus, and a change inintra-thoracic pressure.

In some embodiments, the first therapeutic signal is applied to acomponent of the sympathetic nervous system. In some embodiments, thecomponent of the sympathetic nervous system comprises afferent nervefibers of a splanchnic nerve.

In some embodiments, the second therapeutic signal is configured tomodulate a component of the sympathetic nervous system. In someembodiments, the component of the sympathetic nervous system comprisesefferent fibers in a splanchnic nerve.

In some embodiments, the first therapeutic signal comprises at least oneelectrical pulse train; wherein the at least one electrical pulse trainis applied for a duration ranging from about 2.5 minutes to about 30minutes; wherein the at least one electrical pulse train is followed bya time interval ranging from about 2.5 minutes to about 30 minutesduring which no electrical signal is applied to the component of thenervous system; wherein the at least one electrical pulse traincomprises a frequency ranging from about 0 Hz to about 20 Hz; andwherein the at least one electrical pulse train comprises a currentranging from about 0.1 to about 3 mA.

In some embodiments, the first therapeutic signal comprises a pluralityof electrical pulse trains, wherein pulse trains are separated from eachother by an interval comprising substantially no signal. In someembodiments, at least one of the electrical pulse trains varies induration from the remaining electrical pulse trains. In someembodiments, at least one of the electrical pulse trains varies infrequency from the remaining electrical pulse trains. In someembodiments, at least one of the electrical pulse trains varies incurrent from the remaining electrical pulse trains. In some embodiments,each of the electrical pulse trains are of substantially equal duration.In some embodiments, each of the electrical pulse trains are ofsubstantially equal frequency. In some embodiments, each of theelectrical pulse trains are of substantially equal current.

In some embodiments, the second therapeutic signal comprises at leastone electrical pulse train; wherein the at least one electrical pulsetrain is applied for a duration ranging from about 5 minutes to about120 minutes; wherein the at least one electrical pulse train is followedby a time interval ranging from about 5 minutes to about 180 minutesduring which substantially no electrical signal is applied; wherein theat least one electrical pulse train comprises a frequency ranging fromabout 10 Hz to about 30 Hz; and wherein the at least one electricalpulse train comprises a current ranging from about 1 to about 5 mA.

In some embodiments, the second therapeutic signal comprises a pluralityof electrical pulse trains, and wherein pulse trains are separated fromeach other by an interval comprising substantially no signal. In someembodiments, at least one of the electrical pulse trains varies induration from the remaining electrical pulse trains. In someembodiments, at least one of the electrical pulse trains varies infrequency from the remaining electrical pulse trains. In someembodiments, at least one of the electrical pulse trains varies incurrent from the remaining electrical pulse trains. In some embodiments,each of the electrical pulse trains are of substantially equal duration.In some embodiments, each of the electrical pulse trains are ofsubstantially equal frequency. In some embodiments, each of theelectrical pulse trains are of substantially equal current.

In some embodiments there is provided, an implantable apparatusconfigured to modulate a component of the nervous system of a mammal,the apparatus comprising: a sensor, wherein the sensor is configured toproduce a first sensor output signal associated with the onset of aperiod of nutrient consumption, and a second sensor output signal,associated with the end of a period of nutrient consumption; astimulator configured to output a first therapeutic signal in responseto the first sensor output signal, and a second therapeutic signal inresponse to the second sensor output signal; wherein the firsttherapeutic signal is effective to mimic satiety in the mammal; andwherein the second therapeutic signal is effective to produce anincrease in energy expenditure in the mammal.

In some embodiments, the sensor is configured to produce the firstsensor output signal in response to at least one of swallowing, a bloodglucose level, a neurological signal associated with olfaction, astomach pH level, an electrical impedance of saliva, anelectromyographic signal in the esophagus, and a change inintra-thoracic pressure.

In some embodiments, the sensor is configured to produce the secondsensor output signal in response to at least one of cessation ofswallowing, a blood glucose level, a neurological signal associated withloss of an olfactory signal, a stomach pH level, an electrical impedanceof saliva, an electromyographic signal in the esophagus, and a change inintra-thoracic pressure.

In some embodiments, the first therapeutic signal is applied to acomponent of the sympathetic nervous system. In some embodiments, thecomponent of the sympathetic nervous system comprises afferent nervefibers of a splanchnic nerve.

In some embodiments, the second therapeutic signal is configured tomodulate a component of the sympathetic nervous system. In someembodiments, the component of the sympathetic nervous system comprisesefferent fibers in a splanchnic nerve.

In some embodiments, the apparatus is configured be implanted in thethoracic cavity of the mammal. In some embodiments, the stimulator isconfigured to be programmable after implantation in the mammal.

The novel features of this invention, as well as embodiments of theinvention itself, will be best understood from the attached drawings,taken along with the following description, in which similar referencecharacters refer to similar parts, and in which:

DESCRIPTION OF THE FIGURES

FIG. 1 is a diagram of the efferent autonomic nervous system;

FIG. 2 is a diagram of the sympathetic nervous system;

FIG. 3 is an elevation view of the splanchnic nerves and celiac ganglia;

FIG. 4 is a schematic of an exemplary prior art stimulation patternwhich can be used in the present method of the invention;

FIG. 5 is schematic of an exemplary prior art pulse generator which canbe used in the method of the present invention;

FIG. 6 depicts an exemplary prior art catheter-type lead and electrodeassembly which can be used in the method of the present invention;

FIG. 7 is a graph of known plasma catecholamine levels in response tovarious physiologic and pathologic states;

FIGS. 8A, 8B, and 8C are exemplary graphs of the effect of splanchnicnerve stimulation on catecholamine release rates, epinephrine levels,and energy expenditure, respectively, expected to be achievable in thepractice of the present invention;

FIG. 9 is a graph of known plasma ghrelin level over a daily cycle;

FIG. 10 is a section view of an exemplary instrument placement which canbe used in the method of the present invention for implantation of anelectrode assembly;

FIG. DD1A and DD1B illustrate a first dosing pattern that can bedelivered in some embodiment methods, having an intensity ramp andsubstantially constant frequency over the dose length.

FIG. DD2 is a bar chart having an experimental result from caninesshowing rises in biomarkers using four variations in stimulation.

FIG. DD3 is a bar chart having an experimental result from caninesshowing repeatable rises in biomarkers over a series of three doses.

FIGS. DD4 and DD5 are current and frequency plots for a second dosingalgorithm.

FIGS. DD6 and DD7 are current and frequency plots for a third dosingalgorithm.

DETAILED DESCRIPTION

Weight control can be viewed in relatively simple terms as the netdifference between energy intake and expenditure. Where intake exceedsexpenditure an individual will gain weight over time, and converselywhere expenditure exceeds intake, net weight loss is realized. The goalin any weight control paradigm is thus finding a way in which to reduceintake and/or increase expenditure in order to create a net caloricdeficit. This is the basis of all diet and exercise programs. Whileconceptually simple, for a variety of reasons, most diet and/or exerciseprograms are generally ineffective, typically because of the difficultyin maintaining compliance with the diet and/or exercise regime. However,since appetite and energy expenditure are ultimately regulated by thenervous system, it is hypothetically possible to control weight not byvoluntary adherence to a diet/exercise program, but rather throughdirect modulation of components of the nervous system that are involvedin appetite and metabolism.

The human nervous system is a complex network of nerve cells, orneurons, found centrally in the brain and spinal cord and peripherallyin various nerves of the body. Neurons comprise a cell body, dendritesand an axon. Clusters of neuronal cell bodies are termed ganglia. Anerve is a collection of neurons that are generally organized to serve aparticular part of the body. A single nerve may contain several hundredto several hundred thousand neurons. Nerves often contain both afferentand efferent neurons. Afferent neurons carry signals back to the centralnervous system (CNS) while efferent neurons carry signals away from theCNS to the periphery. Electrical signals are conducted via neurons andnerves. Neurons release neurotransmitters at synapses (connections) withother nerves to allow continuation and modulation of the electricalsignal. In the periphery, synaptic transmission often occurs at ganglia.Nerves can also release transmitters at their termini permittingneuromodulation of target tissues (e.g., adrenal gland).

The electrical signal generated by a neuron is known as an actionpotential. Action potentials are initiated when a voltage potentialacross the neuronal cell membrane exceeds a certain threshold, resultingin the opening of ion channels in the neuronal cell membrane. The actionpotential is then propagated down the length of the neuron. The actionpotential of a nerve is complex and represents the sum of actionpotentials of the individual neurons within it.

Neurons can be myelinated, un-myelinated, of large axonal diameter, orsmall axonal diameter. In general, the speed of action potentialconduction increases with myelination and with neuron axonal diameter.Accordingly, neurons are classified into type A, B and C neurons basedon myelination, axon diameter, and axon conduction velocity. In terms ofaxon diameter and conduction velocity, A conduct faster than B, which inturn conduct faster than C neurons.

The autonomic nervous system is a subsystem of the human nervous systemthat controls involuntary actions of the smooth muscles (blood vesselsand digestive system), the heart, and glands, as shown in FIG. 1. Theautonomic nervous system is divided into the sympathetic andparasympathetic systems. The sympathetic nervous system generallyprepares the body for action by increasing heart rate, increasing bloodpressure, and increasing metabolism. The parasympathetic system preparesthe body for rest by lowering heart rate, lowering blood pressure, andstimulating digestion.

The hypothalamus controls the sympathetic nervous system via descendingneurons in the ventral horn of the spinal cord, as shown in FIG. 2.These neurons synapse with preganglionic sympathetic neurons that exitthe spinal cord and form the white communicating ramus. Thepreganglionic neuron can either synapse in the paraspinous ganglia chainor pass through these ganglia and synapse in a peripheral, orcollateral, ganglion such as the celiac or mesenteric. After synapsingin a particular ganglion, a postsynaptic neuron continues on toinnervate the organs of the body (heart, intestines, liver, pancreas,etc.) or to innervate the adipose tissue and glands of the periphery andskin. Preganglionic neurons of the sympathetic system are typicallymyelinated type A and B neurons, while postganglionic neurons aretypically unmyelinated type C neurons.

Mechano receptors and chemoreceptors in the gut often transmit theirsensory information using frequency encoding, typically over A and Btype fibers. The distended gut can distend the stretch receptors whichgenerate a higher frequency signal when stretched compared to when theyare not stretched, in one example. Nutrient receptors in the gut cangenerate different frequency signals in the presence of a specificnutrient, in another example. These frequency encoded signals travelafferently to the brain, and can indicate fullness and/or the presenceof nutrients.

Several large sympathetic nerves and ganglia are formed by the neuronsof the sympathetic nervous system, as shown in FIG. 3. The greatersplanchnic nerve (GSN) is formed by efferent sympathetic neurons exitingthe spinal cord from thoracic vertebral segment numbers 4 or 5 (T4 orT5) through thoracic vertebral segment numbers 9 or 10 or 11 (T9, T10,or T11). The lesser splanchnic (lesser SN) nerve is formed bypreganglionic sympathetic efferent fibers from T10 to T12 and the leastsplanchnic nerve (least SN) is formed by fibers from T12. The GSN istypically present bilaterally in animals, including humans, with theother splanchnic nerves having a more variable pattern, being presentunilaterally, bilaterally and sometimes even absent.

The splanchnic nerves run along the anterior-lateral aspect of thevertebral bodies and pass out of the thorax entering the abdomen throughthe crus of the diaphragm. The nerves run in proximity to the azygousveins. Once in the abdomen, neurons of the GSN synapse withpostganglionic neurons primarily in celiac ganglia. Some neurons of theGSN pass through the celiac ganglia and synapse on in the adrenalmedulla. Neurons of the lesser SN and least SN synapse withpost-ganglionic neurons in the mesenteric ganglia.

Postganglionic neurons, arising from the celiac ganglia that synapsewith the GSN, innervate primarily the upper digestive system, includingthe stomach, pylorus, duodenum, pancreas, and liver. In addition, bloodvessels and adipose tissue of the abdomen are innervated by neuronsarising from the celiac ganglia/greater splanchnic nerve. Postganglionicneurons of the mesenteric ganglia, supplied by preganglionic neurons ofthe lesser and least splanchnic nerve, innervate primarily the lowerintestine, colon, rectum, kidneys, bladder, and sexual organs, and theblood vessels that supply these organs and tissues.

In the treatment of obesity, one embodiment involves electricalactivation of the greater splanchnic nerve of the sympathetic nervoussystem. In some embodiments unilateral activation can be used, althoughbilateral activation can also be used. The celiac ganglia can also beactivated, as well as the sympathetic chain or ventral spinal roots.

Electrical nerve modulation (nerve activation or inhibition) can beaccomplished by applying an energy signal (pulse), at a certainfrequency, amplitude, and current, to the neurons of a nerve (nervestimulation). Where the energy pulse exceeds the activation thresholdfor neurons in the nerve, those neurons will depolarize, resulting inthe production of action potentials. The cumulative action potential forthe nerve will depend on the extent of recruitment of individual neuronswithin the nerve (i.e., the number of neurons who are provoked todepolarize). The amount of energy applied is a function of the currentamplitude and pulse width duration. Activation or inhibition can be afunction of the frequency, with low frequencies on the order of 1 to 50Hz resulting in activation, and high frequencies greater than 100 Hzgenerally resulting in inhibition. Inhibition can also be accomplishedby continuous energy delivery resulting in sustained depolarization,which leads to neuronal accommodation (de-sensitization). Differentneuronal types may respond to different frequencies and energies withactivation or inhibition.

Each neuronal type (A, B, or C neurons) has a characteristic pulseamplitude-duration profile (energy pulse signal) that leads toactivation. Myelinated neurons (types A and B) can generally bestimulated with relatively low current amplitudes on the order of 0.1 to5.0 milliamperes, and short pulse widths on the order of 50 to 200microseconds. Unmyelinated type C fibers typically require longer pulsewidths, on the order of 300 to 1,000 microseconds, and higher currentamplitudes. This difference in energy for activation can beadvantageously exploited in order to selectively stimulate certainsubsets of neurons in a nerve containing mixed neuronal types. This isof particular use in modulating nerves such as the splanchnic, as thesplanchnic nerves contains both afferent pain neurons, which aretypically type C neurons, and efferent preganglionic neurons, which aremyelinated type B neurons. Thus, in a therapy such as obesity treatmentinvolving splanchnic nerve activation, it is desirable to activate theefferent type B neurons and not the afferent type C pain neurons. Thiscan be effectively accomplished by varying the energy pulse signal.

A fibers are an integral part of the afferent stimulation and signaling.The A fibers can be activated at relatively low stimulation intensityand are often activated in early, lower current portions of sometherapies and doses according to the present invention.

Two important parameters related to stimulation of peripheral nerves ofmixed neuronal type are the rheobase and chronaxie. These two parametersare a function of the stimulus duration and stimulus strength (currentamplitude). The rheobase is the lower limit of the stimulus strengthbelow which an action potential cannot be generated, regardless of thestimulus duration. The chronaxie is the stimulus duration correspondingto twice the rheobase. This is a measure of excitability of the mixedperipheral nerve. It is generally not desirable to stimulate aperipheral nerve at stimulus intensities greater than the chronaxie. Thechronaxie of the splanchnic nerve is estimated to be betweenapproximately 150 microseconds and 400 microseconds.

Various stimulation patterns, ranging from continuous to intermittent,can be utilized. With intermittent stimulation, energy is delivered fora period of time at a certain frequency during the signal-on time asshown in FIG. 4. The signal-on time is followed by a period of time withno energy delivery, referred to as signal-off time.

Superimposed on the stimulation pattern are the parameters of pulsefrequency and pulse duration. The treatment frequency may be continuousor delivered at various time periods within a day or week. The treatmentduration may last for as little as a few minutes to as long as severalhours. For example, in some embodiments splanchnic nerve activation totreat obesity may be delivered at a frequency of three times daily,coinciding with meal times. Treatment duration with a specifiedstimulation pattern may last for one hour. Alternatively, treatment maybe delivered at a higher frequency, say every three hours, for shorterdurations, say 30 minutes. The treatment duration and frequency can betailored to achieve the desired result.

In some embodiments, neural activation by an electrical stimulator isregulated by an output signal received from a sensor. The sensor mayeither be external, or internally implanted in the subject. In someembodiments, the sensor is configured to detect swallowing indicative ofthe consumptions of food. In some embodiments, the sensor may beconfigured to produce an output signal in response to, and without beinglimiting, a change in blood glucose levels, a neurological signalassociated with olfaction (i.e., the smell of food), a change in stomachpH (indicating the presence of food and release of stomach acid as partof the digestion process), a change in impedance in the saliva of theoral cavity, detection of an electromyographic signal in or near theesophagus indicative of swallowing, and a change in intrathoracicpressure detected for example by a sensor placed at the suprasternalnotch.

Upon sensing a swallowing event, the sensor is configured to produce anoutput signal that can be relayed directly or via remote means (e.g.,wirelessly) to a neural stimulator, which in turn will respond to thesensor signal by applying a signal to a component of the nervous system,such as a splanchnic or other nerve, or directly to a portion of thegastrointestinal tract. In some embodiments, the signal, which in thiscase can be described as a first therapeutic signal, can be configuredwith respect to frequency, amplitude, and duration to mimic satiety andinduce the subject to either reduce or cease food intake on feeling asense of fullness. In some embodiments, the first therapeutic signal cantake the form of a train of electrical pulses. A pulse train can rangein duration from about 2.5 minutes to about 60 (or 30 in anotherembodiment) minutes; pulse frequency can range from about 0 Hz to about20 Hz; and pulse current can range from about 1 to about 5 mA.

In some embodiments, the first therapeutic signal can comprises aplurality of such pulse trains, which may be of equal or varyingduration, frequency, or current amplitude. In some embodiments, pulseenergy (total power inherent in a pulse train) can be ramped up or downover time in order to effectively titrate the response of the nervoussystem to the applied neuromodulatory signal.

In some embodiments, individual pulse trains can be separated by aperiod of no stimulation greater, lesser, or equal to the length of apulse train. In addition, the first therapeutic signal can be configuredto terminate upon cessation of eating, or can be continued for a periodof time following eating in order to ensure that the subject does notresume food consumption until a period of time has elapsed.

Pulse generation for electrical nerve modulation can be accomplishedusing a pulse generator. Pulse generators can use conventionalmicroprocessors and other standard electrical components. A pulsegenerator for this embodiment can generate a pulse, or energy signal, atfrequencies ranging from approximately 0 Hz (i.e., constant current) to300 Hz, a pulse width from approximately 10 to 1,000 microseconds, and aconstant current of between approximately 0.1 milliamperes to 20milliamperes. The pulse generator can be capable of producing a ramped,or sloped, rise in the current amplitude and/or frequency. In someembodiments, a pulse generator can communicate with an externalprogrammer and/or monitor. Passwords, handshakes and parity checks canbe employed for data integrity. The pulse generator can be batteryoperated or operated by an external radiofrequency device. Because thepulse generator, associated components, and battery may be implantedthey are preferably encased in an epoxy-titanium shell.

A schematic of an implantable pulse generator (IPG) is shown in FIG. 5.Components can be housed in the epoxy-titanium shell. A battery suppliespower to the logic and control unit. A voltage regulator controls thebattery output. A logic and control unit can control the stimulus outputand allow for programming of the various parameters such as pulse width,amplitude, and frequency. In addition, stimulation pattern and treatmentparameters can be programmed at the logic and control unit. A crystaloscillator provides timing signals for the pulse and for the logic andcontrol unit. An antenna is used for receiving communications from anexternal programmer and for status checking the device. An outputsection couples to the electrodes and leads that carry the energy pulseto the nerve. A reed switch allows manual activation using an externalmagnet. Devices powered by an external radiofrequency device can be usedto limit the components to primarily a receiving coil or antenna.

The IPG can be coupled to a lead and electrode assembly. The lead cancomprise a bundle of electrically conducting wires insulated from thesurroundings by a non-electrically conducting coating. Where used, wiresof the lead connect the IPG to the stimulation electrodes, whichtransfers the energy pulse to the nerve. A single wire may connect theIPG to the electrode, or a wire bundle may connect the IPG to theelectrode. Wire bundles may or may not be braided. Wire bundles arepreferred because they increase reliability and durability.Alternatively, a helical wire assembly could be utilized to improvedurability with flexion and extension of the lead. In some embodiments,power could be transmitted from the pulse generator to an end effectorelectrode wirelessly.

The electrodes can comprise platinum or platinum-iridium ribbons orrings as shown in FIG. 6. The electrodes are capable of electricallycoupling with the surrounding tissue and nerve. The electrodes mayencircle a catheter-like lead assembly. The distal electrode may form arounded cap at the end to create a bullet nose shape. Ideally, thiselectrode serves as the cathode. A lead of this type may contain 2 to 4ring electrodes spaced anywhere from 2.0 to 5.0 mm apart with each ringelectrode being approximately 1.0 to 10.0 mm in width. Catheter leadelectrode assemblies may have an outer diameter of 0.5 mm to 1.5 mm tofacilitate percutaneous placement using an introducer.

Bipolar stimulation of a nerve can be accomplished with multipleelectrode assemblies with one electrode serving as the positive node andthe other serving as a negative node. In this manner nerve activationcan be directed primarily in one direction (unilaterally), for example,to selectively activate efferent nerve fibers. Alternatively, a nervecuff electrode can be employed. Helical cuff electrodes, such as thosedescribed in U.S. Pat. No. 5,251,634 (Weinberg), can be used. Cuffassemblies can similarly have multiple electrodes and direct and causeunilateral nerve activation.

Unipolar stimulation can also be performed. As used herein, unipolarstimulation means using only a single electrode on the lead, while themetallic shell of the IPG, or another external portion of the IPG,essentially functions as a second electrode, remote from the firstelectrode. In some embodiments, unipolar stimulation may be moresuitable for splanchnic nerve stimulation than the bipolar stimulationmethod, particularly if the electrode is to be placed percutaneouslyunder fluoroscopic visualization. With fluoroscopically observedpercutaneous placement, it may not always be possible to place theelectrodes immediately adjacent the nerve, which is often required forbipolar stimulation.

With unipolar stimulation, a larger energy field is created in order toelectrically couple the electrode on the lead with the remote externalportion of the IPG, and the generation of this larger energy field canresult in activation of the nerve even in the absence of close proximitybetween the single lead electrode and the nerve. This allows successfulnerve stimulation with the single electrode placed only in “generalproximity” of the nerve. This allows for significantly greaterseparation between the electrode and the nerve than the “closeproximity” required for effective bipolar stimulation. The magnitude ofthe allowable separation between the electrode and the nerve willnecessarily depend upon the actual magnitude of the energy field thatthe stimulator generates with the lead electrode in order to couple withthe remote electrode. Patch electrodes, cuff electrodes, andtransvascular/intravascular electrodes may be used in variousembodiments.

In multiple electrode assemblies, some of the electrodes may be used forsensing nerve activity. This sensed nerve activity could serve as asignal to commence stimulation therapy. For example, afferent actionpotentials in the splanchnic nerve, created due to the commencement offeeding, could be sensed and used to activate the IPG to beginstimulation of the efferent neurons of the splanchnic nerve. Appropriatecircuitry and logic for receiving and filtering the sensed signal wouldbe required in the IPG. Thus, in some embodiments, electrodes within theassembly can be used to provide the sensor functionality as describedherein with respect to detecting swallowing or some other physiologicalparameter associated with eating as has been described above.

Because branches of the splanchnic nerve directly innervate the adrenalmedulla, electrical activation of the splanchnic nerve results in therelease of catecholamines (epinephrine and norepinephrine) into theblood stream. In addition, dopamine and cortisol, which also raiseenergy expenditure, can be released. Catecholamines can increase energyexpenditure by 15% to 20%. By comparison, subitramine, a pharmacologicagent used to treat obesity, increases energy expenditure by only 3% to5%.

Human resting venous blood levels of norepinephrine and epinephrine areapproximately 300 picograms (pg)/milliliter (ml) and 25 pg/ml,respectively, as shown in FIG. 7. Detectable physiologic changes such asincreased heart rate occur at norepinephrine levels of approximately1,500 pg/ml and epinephrine levels of approximately 50 pg/ml. Venousblood levels of norepinephrine can reach as high 2,000 pg/ml duringheavy exercise, and levels of epinephrine can reach as high as 400 to600 pg/ml during heavy exercise. Mild exercise produces norepinephrineand epinephrine levels of approximately 500 pg/ml and 100 pg/ml,respectively. It may be desirable to maintain catecholamine levelssomewhere between mild and heavy exercise during electrical sympatheticactivation treatment for obesity.

In anesthetized animals, electrical stimulation of the splanchnic nervehas shown to raise blood catecholamine levels in a frequency dependentmanner in the range of 1 Hz to 20 Hz, such that rates of catecholaminerelease/production of 0.3 to 4.0 mug/min can be achieved. These ratesare sufficient to raise plasma concentrations of epinephrine to as highas 400 to 600 pg/ml, which in turn can result in increased energyexpenditure ranging from 10% to 20% as shown in FIG. 8. Duringstimulation, the ratio of epinephrine to norepinephrine is 65% to 35%.It may be possible to change the ratio by stimulating at higherfrequencies. This may be desired to alter the energy expenditure and/orprevent a rise in MAP.

Energy expenditure in humans ranges from approximately 1.5 kcal/min to2.5 kcal/min. A 15% increase in this energy expenditure in a person withan expenditure of 2.0 kcal/min would increase energy expenditure by 0.3kcal/min. Depending on treatment parameters, this could result in anadditional 100 to 250 kcal of daily expenditure and 36,000 to 91,000kcal of yearly expenditure. One pound of fat is approximately 3500 kcal,yielding an annual weight loss of 10 to 26 pounds.

Increased energy expenditure is typically fueled by fat and carbohydratemetabolism, and in extreme cases of weight loss by metabolism ofprotein. Postganglionic branches of the splanchnic nerve innervate theliver and fat deposits of the abdomen. Activation of the splanchnicnerve can result in fat metabolism and the liberation of fatty acids, aswell as glycogen breakdown and the release of glucose from the liver.Fat metabolism coupled with increased energy expenditure may result in anet reduction in fat reserves.

The present invention takes advantage of the known relationship betweensympathetic activation and energy expenditure. As a result, in someembodiments, a second therapeutic signal can be produced that isconfigured to increase energy expenditure. The second therapeutic signalcan be generated in response to the sensing of the end of a period ofeating. This can be, for example, after the cessation of a patter ofswallowing typical of eating, upon achieving a desired blood glucoselevel, upon loss of olfactory signals, where stomach pH begins to rise,a change in impedance of saliva in the oral cavity, or a cessation ofchanges in intrathoracic pressure detected in the vicinity of thesuprasternal notch. Alternatively, the second therapeutic signal couldbe generated upon cessation of electromyographic signals on or near theesophagus that are normally associated with swallowing of food. In someembodiments the second therapeutic signal may be generated immediatelyafter the end of a meal period. In some embodiments, the secondtherapeutic signal may be delayed in time until some pre-determined timefollowing eating, or in response to sensing some pre-determinedphysiological parameter (e.g., catecholamine levels, blood glucoselevels, signaling molecule levels).

Analogously to the first therapeutic signal, the second therapeuticsignal can be configured, without limitation, with respect to duration,frequency, and current amplitude. Similarly, the second therapeutic canbe applied in the form of an electrical pulse train, or plurality ofsuch pulse trains. Pulse trains can be of similar or varying duration,frequency, and/or current amplitude. In some embodiments, an electricalpulse train can comprise a duration ranging from about 5 to about 120minutes, a frequency ranging from about 10 to about 30 Hz, and a currentamplitude ranging from about 1 to about 5 mA. In some embodiments, pulsetrains within a plurality of pulse trains can be separated from eachother by period during which no signal is applied. These intervals canbe of greater, lesser, or equal duration to individual pulse trains.

In some embodiments, signal intensity of the second therapeutic signalcan be ramped up or down as desired in order to achieve a desiredphysiological parameter or outcome. For example, and without beinglimiting, signal intensity may be modulated in order to maintain bloodglucose levels, or catecholamine levels (or as described below to levelsof ghrelin or some other signaling molecule), at concentrations thatenhance increased energy expenditure, in effect providing a way oftitrating neuromodulation to achieve a desired result.

It may also be desirable to titrate obesity therapy to plasma ghrelinlevels. In humans, venous blood ghrelin levels range from approximately250 pg/ml to greater than 700 pg/ml as shown in FIG. 9. Ghrelin levelsrise and fall during the day with peak levels typically occurring justbefore meals. In patients with gastric bypass surgery, an effectivetreatment for obesity, ghrelin levels are more static and typically stayin a low range of 100 to 200 pg/ml. Splanchnic nerve activation, in thetreatment of obesity, could be titrated to keep ghrelin levels in thelow range below 250 to 300 pg/ml. Reductions in food intake comparableto the increases in energy expenditure (i.e., 100 to 250 kcal/day),could yield a total daily kcal reduction of 200 to 500 per day, and 20to 50 pounds of weight loss per year.

In anesthetized animals, electrical activation of the splanchnic nervehas also been shown to decrease insulin secretion. In obesity, insulinlevels are often elevated, and insulin resistant diabetes (Type II) iscommon. Down-regulation of insulin secretion by splanchnic nerveactivation may help correct insulin resistant diabetes.

Electrical activation of the splanchnic nerve can cause an increase inmean arterial blood pressure (MAP) above a baseline value. A drop in MAPbelow the baseline can follow this increase. Because a sustainedincrease in MAP is undesirable, the stimulation pattern can be designedto prevent an increase in MAP. One strategy would be to have arelatively short signal-on time followed by a signal-off time of anequal or longer period. This would allow the MAP to drop back to orbelow the baseline. The subsequent signal-on time would then raise theMAP, but it may start from a lower baseline. In this manner asinusoidal-like profile of the MAP could be set up during therapydelivery that would keep the average MAP within safe limits. The rise inMAP can be accompanied by a decrease in heart rate which is acompensatory mechanism that may also normalize MAP with sustainedstimulation for more than approximately 10 minutes.

Alternatively, in some embodiments, an alpha-sympathetic receptorblocker, such a prazosin could be used to blunt the rise in MAP.Alpha-blockers are commonly available antihypertensive medications. Therise in MAP seen with splanchnic nerve stimulation is the result ofalpha-receptor activation, which mediates arterial constriction. Becausethe affects of this therapy on reduced food intake and energyexpenditure are related to beta-sympathetic receptor activity, additionof the alpha-blocker would not likely alter the therapeutic weight lossbenefits. Given the potential for relatively short period of stimulationwith the present method, however, it may be possible to avoid altogetherthe increase in MAP that attends other stimulatory programs, anadditional advantage provided by the present invention.

Implantation of the lead/electrode assembly for activation of thegreater splanchnic nerve can ideally be accomplished percutaneouslyusing an introducer as shown in FIG. 10. The introducer can be a hollowneedle-like device that would be placed posteriorly through the skinbetween the ribs para-midline at the T9-T12 level of the thoracic spinalcolumn. A posterior placement with the patient prone is preferred toallow bilateral electrode placement at the splanchnic nerves, ifrequired. Placement of the needle could be guided using fluoroscopy,ultrasound, or CT scanning. Proximity to the splanchnic nerve by theintroducer could be sensed by providing energy pulses to the introducerto electrically activate the nerve while monitoring for a rise in MAP.All but the very tip of the introducer would be electrically isolated soas to focus the energy delivered to the tip of the introducer. The lowerthe current amplitude required to cause a rise in the MAP, the closerthe introducer tip would be to the nerve. Ideally, the introducer tipserves as the cathode for stimulation.

Alternatively, a stimulation endoscope could be placed into the stomachof the patient for electrical stimulation of the stomach. The evokedpotentials created in the stomach could be sensed in the splanchnicnerve by the introducer. To avoid damage to the spinal nerves, theintroducer could sense evoked potentials created by electricallyactivating peripheral sensory nerves. Once the introducer was inproximity to the nerve, a catheter type lead electrode assembly would beinserted through the introducer and adjacent to the nerve.

Percutaneous placement of the lead electrode assembly could be enhancedusing direct or video assisted visualization. An optical port could beincorporated into the introducer. A separate channel would allow theelectrode lead assembly to be inserted and positioned, once the nervewas visualized. Alternatively, a percutaneous endoscope could beinserted into the chest cavity for viewing advancement of the introducerto the nerve. The parietal lung pleuron is relatively clear, and thenerves and introducer can be seen running along the vertebral bodies.With the patient prone, the lungs are pulled forward by gravity creatinga space for the endoscope and for viewing. This may avoid the need forsingle lung ventilation. If necessary, one lung could be collapsed toprovide space for viewing. This is a common and safe procedure performedusing a bifurcated endotracheal tube. The endoscope could also be placedlaterally, and positive CO₂ pressure could be used to push down thediaphragm, thereby creating a space for viewing and avoiding lungcollapse.

Alternatively, stimulation electrodes could be placed along thesympathetic chain ganglia from approximately vertebra T4 to T11. Thisimplantation could be accomplished in a similar percutaneous manner asabove. This would create a more general activation of the sympatheticnervous system, though it would include activation of the neurons thatcomprise the splanchnic nerves.

Alternatively, the lead/electrode assembly could be placedintra-abdominally on the portion of the splanchnic nerve that residesretroperitoneally on the abdominal aorta just prior to synapsing in theceliac ganglia. Access to the nerve in this region could be accomplishedlaparoscopically, using typical laparoscopic techniques, or via openlaparotomy. A cuff electrode could be used to encircle the nerveunilaterally or bilaterally. The lead could be anchored to the crus ofthe diaphragm. A cuff or patch electrode could also be attached to theceliac ganglia unilaterally or bilaterally. Similar activation of thesplanchnic branches of the sympathetic nervous system would occur asimplanting the lead electrode assembly in the thoracic region.

An alternative lead/electrode placement can be via a transvascularapproach. Due to the proximity of the splanchnic nerves to the azygousveins shown in FIG. 10, and in particular the right splanchnic nerve andright azygous vein, modulation could be accomplished by positioning alead/electrode assembly in this vessel. The venous system and azygousvein can be accessed via the subclavian vein using standard techniques.The electrode/lead assembly can be mounted on a catheter. A guidewirecan be used to position the catheter in the azygous vein. Thelead/electrode assembly would include an expandable member, such as astent. The electrodes can be attached to the stent, and using balloondilation of the expandable member, can be pressed against the vesselwall so that energy delivery can be transferred to the nerve. Anexpandable member would allow fixation of the electrode lead assembly inthe vessel. The IPG and remaining lead outside of the vasculature can beimplanted subcutaneously in a manner similar to a heart pacemaker.

Various doses can be delivered in response to the detection of eating.Three different dosing strategies are described below. Individual ormultiple doses from these strategies may be utilized as part of variousembodiments of the present invention.

FIGS. DD1A and DD1B illustrate one algorithm according to the presentinvention. In this algorithm, labeled as “Algorithm A” in the figure,the series of doses are delivered in a diurnal pattern, are deliveredduring typical waking hours, and are not delivered in the typicalsleeping hours. In this example, the doses are delivered about 12 timesper day. The doses are about a half hour long, with an inter-dose no (orsubstantially reduced intensity) stimulation period of about one hour inbetween. Algorithm A, in this example, has a substantially constantfrequency, of about 20 Hz. The stimulation intensity ramps up at thebeginning of the dose, ramps down at the end of the dose, and has asubstantially constant intensity plateau portion in between the up rampand down ramp.

The intensity is shown as a percent of Maximum Tolerable Current (MTC),a measure of tolerable stimulation intensity. MTC can be measured invarious ways, depending on the embodiment. In one embodiment, thepatient is stimulated at various intensities and asked which intensityis the maximum they could tolerate after leaving the session. In anothermethod, which can be used in animals and humans, the blood pressure isobserved during stimulation and compared to a blood pressure base linethe day before the stimulation. The Mean Arterial Pressure (MAP) may beused, which may be approximated as ⅓ times the systolic plus ⅔ times ofthe diastolic, to give each a proper weighting. A MTC in this embodimentmay be the intensity at which MAP increases 20 percent above thebaseline.

In one embodiment, the pulse width is held at about ½ ms (500 usec)while the current is varied. In another embodiment, the current is heldconstant while the pulse width is varied. In still other embodiments,both current and pulse width are varied to vary the pulse width*currentproduct, which is the intensity, having units of time*current which ischarge, typically mSec*mA. In some embodiments the MTC has a pulse widthof about ½ msec (512 usec in one embodiment) and a current of about 1,2, or even 3 mA.

In FIGS. DD1A and DD1B, the current increases in a ramp over the first10 minutes, holds constant for 15 minutes, and decreases over the next 5minutes. This is followed by 60 minutes of no stimulation, followed byanother dose, during typical waking hours. In the embodimentillustrated, the first dose occurs at 4:00 and the last dose stops atabout 21:00. In this embodiment, the first dose occurs in pre-wakinghours, which may act to inhibit morning appetite and/or stimulatemetabolism prior to waking In some embodiments, the first dose does notoccur until the patient is normally awake, and the last dose ends atleast about one, two, or three hours before sleep is expected, invarious embodiments.

Algorithm A thus has a dose time of at least about 15 minutes and lessthan about 60 minutes, or at least about 20 minutes and less than 40minutes, or between about 20 and 30 minutes, or about a half hour. Theinter dose interval can last at least about one half hour and less thanabout 3 hours, or at least about ¾ hour and less than about 2 hours, orat least about one hour and less than about two hours, and combinationsthereof. The dose can act to drive a sensation of satiety and/orincrease metabolism for a period sufficient to initiate this sensationand metabolic rate increase, but not so long as to significantly reducethe same effects later, when the dose is repeated again. The dose lengthcan be such that there is no short term degradation in the response. Thedose length can be such that there is no decrease in an otherwiseincreasing biomarker, for example, Free Fatty Acids (FFA), Glucagon,Glycerol, and Glucose, during the dose. This can be explicitly measuredon a per patient basis or based on the expected response for a patient,based on other patient responses. In this way, the same dose deliveredagain during the day can have the same effective result, rather than ablunted response as previous excessive stimulation has caused anaccommodation response by the body. The diurnal, lack of stimulationduring sleeping hours may also aid in the anti-accommodation performanceof the therapy. In this way, the same dose delivered a day later willhave substantially the same physiological response as the dose theprevious day.

FIG. DD2 illustrates the beneficial effect of even short stimulationdoses (of 5-7 minutes) followed by about a half hour of off-time. Theincreases in Free Fatty Acids (FFA), Glucagon, Glycerol, and Glucose(GLU) are all seen.

FIG. DD3 illustrates the beneficial effect of a 30 minute dose having a60 minute inter-dose interval in between. This stimulation used a 60second on/60 second off duty cycle, at 2 mA and 20 Hz. The change inglycerol and FFA both at 10 minutes after the start of the dose are seento be significant. The liberation of FFA and glycerol, indicative oflipolysis, is seen to repeat in doses 2 and 3. This indicates there issome recovery and lack of significant accommodation to the repeateddoses. There may well be beneficial effects in addition to the burningof fat stores. The circulating FFA and glucose which result from thedose may well reduce appetite as well, as glucose is added to the bloodstream and sensed, for example, by the brain. This can thereby reducehunger and blunt appetite, apart from any direct satiety signaling bythe dose, and lasting after the dose has ceased.

FIG. DD4 illustrates another family or group of algorithms, labeled as“Algorithm B” in the figures. In this algorithm, the current is heldsubstantially constant, while the frequency is ramped up and down in adose. In this example, intensity (here current) is held constant for ahalf hour period, while frequency is ramped up and down for three rampswithin a half hour long dose. In this example, current is held at 100percent of MTC, while the frequency ramp is a linear ramp from 0 to 20Hz for 5 minutes, then a ramp down from 20 Hz to 0 over 5 minutes, thentwo repeats of same. The inter-dose interval can be about 60 minutes, orthe same times discussed with respect to Algorithm A, both for the dosesand inter-dose intervals. The duty cycle can be 5 seconds on and 5seconds off, in some embodiments.

FIG. DD5 shows the doses delivered over a day, for the entire day andnight. In some embodiments, stimulation is stopped during expectedsleeping hours.

Algorithm B can be used to deliver variations of afferent signalingwhich may mimic the nutrient and mechanoreceptors which normallyindicate the presence of food. The increasing and/or decreasing may aidin overcoming or preventing accommodation to the stimulation. Differentpopulations of neurons may be effectively stimulated by differentfrequencies at the different times into each frequency ramp. In variousembodiments, the dose/inter-dose times may be 10/20, 30/60, 80/160, andthe like, with the times given in minutes. The frequency increasingportions may be about 5, 10, or 15 minutes long in some embodiments, asmay the frequency decreasing portions in some embodiments. The frequencyramp portions can be configured such that the subsequent frequency rampshave substantially similar results as the first such ramps in the doseand/or compared to the same ramp in the next dose.

FIGS. DD5 and DD6 illustrate another algorithm, labeled “Algorithm C.”The dose and inter-dose times can be as previously described withrespect to Algorithms B and C. Algorithm C can have a substantiallyconstant stimulation intensity, shown here as 100 percent of MTC.Algorithm C can also have an increasing frequency ramp portion followedby a substantially constant frequency portion, followed by a decreasingfrequency ramp portion. In this example, the frequency increases fromabout 0 to 20 Hz over about 15 minutes, then remains at about 20 Hz for35 minutes, and then decreases back to about 0 Hz over about 10 minutes.In some embodiments, the frequency ramp up is about ¼ hour, the constantportion about ½ hour, and the ramp down about ¼ hour. In this example,the stimulation can either be run day and night or discontinued inexpected sleeping times.

Algorithm C may be viewed as a combination or blending of algorithms Aand B. The frequency ramp up, plateau and ramp down are believed to atleast partially replicate normally satiety curves as induced by a mealfollowed by a normal post meal decline, as seen by the nutrient andmechano receptors in the stomach and lower gut. Such mimicry can be usedto sneak under the body's accommodation response that could otherwisereduce response to subsequent doses.

Other algorithms may also be used in some aspects of the presentinvention. Algorithm C can be varied having an 80 minute dose and a 160minute inter-dose interval, with a 30 minute current ramp to maximumdose. The 30 minute ramp may provide a beneficial CV response at thedose onset, and has shown that in some tests. In another embodiment,Algorithm A is varied, to have a 30 min dose/60 minute inter-doseinterval, with 24 hour application.

While the particular invention as herein shown and disclosed in detailis fully capable of obtaining the objects and providing the advantageshereinbefore stated, it is to be understood that this disclosure ismerely illustrative of the presently preferred embodiments of theinvention and that no limitations are intended other than as describedin the appended claims.

PATENTS CONSIDERED

U.S. Pat. No. 5,188,104U.S. Pat. No. 6,735,477U.S. Pat. No. 6,993,391U.S. Pat. No. 7,177,693U.S. Pat. No. 7,330,753U.S. Pat. No. 7,437,195

US Application 2002-0161414 US Application 2003-0144708 US Application2004-0059393 US Application 2004-0193229 US Application 2005-0222638 USApplication 2006-0020298 US Application 2006-0129201 US Application2006-0161217 US Application 2007-0106337 US Application 2007-0162085 USApplication 2008-0147139 US Application 2008-0154329 US Application2008-0161875 US Application 2008-0183238 US Application 2007-0299320International Application WO 2008 103077

International Application WO 2008 117296

1. A method of modulating a component of the nervous system of a mammal,the method comprising: providing a sensor, wherein the sensor isconfigured to produce a first sensor output signal associated with theonset of a period of nutrient consumption, and a second sensor outputsignal, associated with the end of a period of nutrient consumption;providing a stimulator configured to output a first therapeutic signalin response to the first sensor output signal, and a second therapeuticsignal in response to the second sensor output signal; wherein applyingthe first therapeutic signal to a first component of the nervous systemis effective to mimic satiety in the mammal; and wherein applying thesecond therapeutic signal to a second component of the nervous system iseffective to produce an increase in energy expenditure in the mammal. 2.The method of claim 1, wherein the sensor is configured to produce thefirst sensor output signal in response to at least one of swallowing, ablood glucose level, a neurological signal associated with olfaction, astomach pH level, an electrical impedance of saliva, anelectromyographic signal in the esophagus, and a change in intrathoracicpressure.
 3. The method of claim 1, wherein the sensor is configured toproduce the second sensor output signal in response to at least one ofcessation of swallowing, a blood glucose level, a neurological signalassociated with loss of an olfactory signal, a stomach pH level, anelectrical impedance of saliva, an electromyographic signal in theesophagus, and a change in intra-thoracic pressure.
 4. The method ofclaim 1, wherein the first therapeutic signal is applied to a componentof the sympathetic nervous system.
 5. The method of claim 1, wherein thecomponent of the sympathetic nervous system comprises afferent nervefibers of a splanchnic nerve.
 6. The method of claim 1, wherein thesecond therapeutic signal is configured to modulate a component of thesympathetic nervous system.
 7. The method of claim 6, wherein thecomponent of the sympathetic nervous system comprises efferent fibers ina splanchnic nerve.
 8. The method of claim 1, wherein the firsttherapeutic signal comprises at least one electrical pulse train;wherein the at least one electrical pulse train is applied for aduration ranging from about 2.5 minutes to about 30 minutes; wherein theat least one electrical pulse train is followed by a time intervalranging from about 2.5 minutes to about 30 minutes during which noelectrical signal is applied to the component of the nervous system;wherein the at least one electrical pulse train comprises a frequencyranging from about 0 Hz to about 20 Hz; wherein the at least oneelectrical pulse train comprises a current ranging from about 1 to about5 mA.
 9. The method of claim 8, wherein the first therapeutic signalcomprises a plurality of electrical pulse trains, wherein pulse trainsare separated from each other by an interval comprising substantially nosignal. 10-32. (canceled)
 33. A method of modulating a component of thenervous system of a mammal, the method comprising: sensing the onset ofeating in the mammal; and stimulating a splanchnic nerve responsive tothe eating sensing by applying at least one electrical stimulus dose, inwhich the dose has a stimulation duration of at least about ¼ hour andhas a frequency which varies much more than the intensity; in which themethod has a reduced intensity or no intensity interval after the doseat least about 1 hour in length.
 34. The method of claim 33, in whichthe dose stimulation duration is less than about 1 hour.
 35. The methodof claim 34, in which the dose stimulation duration is less than about ½hour.
 36. The method of claim 33, in which the dose frequency increasesat the beginning of the dose for at least about ⅕ of the dose anddecreases at the end of the dose for at least about ⅕ of the dose. 37.The method of claim 36, in which the dose frequency remainssubstantially constant in the middle of the dose for at least about ⅕ ofthe dose.
 38. The method of claim 33, in which the dose frequencyincreases and decreases over the dose in a pattern which mimics a normaleating response.
 39. The method of claim 33, in which the dose frequencyhas a maximum frequency in the dose in between about 10 Hz and 20 Hz.40. The method of claim 33, in which the dose stimulation intensity hasa maximum intensity in between about ½ mSec-mA and about 2 mSec-mA. 41.The method of claim 33, in which the dose stimulation intensity andfrequency are configured sufficient to raise biomarkers indicative ofeating food to levels substantially the same or least half of the levelindicative of eating food.
 42. The method of claim 41, in which the dosestimulation duration is sufficient to raise biomarkers indicative ofeating food to levels substantially the same or least half of the levelindicative of eating food, and the stimulation stops or substantiallyreduces upon the biomarkers raising to the level indicative of eatingfood. 43-52. (canceled)
 53. A method of modulating a component of thenervous system of a mammal, the method comprising: sensing the onset ofeating in the mammal; and stimulating a splanchnic nerve responsive tothe eating sensing by applying at least one electrical stimulus firstdose, in which the first dose has a stimulation duration of at leastabout ¼ hour and has a frequency which varies much more than theintensity; in which the method follows the varying frequency first dosewith an increasing intensity second dose configured to stimulate moreefferently than the first dose and to capture more fibers than the firstdose.